Individuals of similar body size may differ widely in their risk of cardiovascular disease (CVD), suggesting that factors other than body mass index or total body adiposity are key determinants of adiposity-associated CVD risk. Deposition of triglyceride in lean tissues (ectopic fat) can occur in the liver, heart, muscle, pancreas, and kidneys and is associated with various forms of morbidity, including CVD. The location of the fat may determine its impact on CVD risk. Adipocytokines, hormones released by adipose tissue, appear to be associated with both vascular disease and the deposition of fat in lean tissues, even in non-obese individuals. However, little is known regarding the potentially differential effects of fat in the heart vs. liver on cardiometabolic risk factors, adipocytokine profiles, or atherosclerosis, and their independence from body size or waist girth measures. Additionally, the extent to which menopausal hormone therapy (MHT) may alter adipocytokine and ectopic fat levels is not known. This study proposes to fill these gaps in knowledge by examining the relationships of hepatic and cardiac fat deposition with the progression of atherosclerosis in postmenopausal women. In addition, it will provide novel information concerning the effects of MHT on adiposity, adipocytokines, and ectopic fat. This application takes advantage of participants, specimens, and data from a fully enrolled, ongoing clinical trial of 728 women called the Kronos Early Estrogen Prevention Study (KEEPS). KEEPS is a randomized, placebo-controlled clinical trial examining the effects of MHT given to recently postmenopausal women on atherosclerosis progression. The central hypothesis of this ancillary application is that the location of fat, rather than body size or total adiposity, is an important determinant of cardiometabolic abnormalities and atherosclerosis, and the primary goal of this project is to identify the fat locations which carry the greatest atherogenic potential. The specific aims are: 1.) To examine the crosssectional relationships between fat in different locations (liver, epicardium, pericardium) with cardiometabolic risk factors, adipocytokines, and subclinical atherosclerosis;2.) To identify the impact of oral and transdermal MHT vs. placebo on ectopic fat measures and adipocytokines, and 3).To examine the longitudinal relationships between fat in different locations with changes in cardiometabolic risk factors, adipocytokines, and subclinical atherosclerosis. The proposed study will generate information which will assist in better stratifying CVD risk in women and lead to improved treatment strategies, including perhaps MHT, to reduce risk in both obese and non-obese women. This, in turn, should lead to targeting of prevention and treatment efforts to those women (lean or obese) with the greatest risk of CVD in a manner tailored to their individual metabolic and adipose tissue profiles.